Cell Death in Pancreatitis

Abstract

Mechanisms of cell death in pancreatitis remain unknown. Parenchymal necrosis is a major complication of pancreatitis; also, the severity of experimental pancreatitis correlates directly with necrosis and inversely with apoptosis. Thus, shifting death responses from necrosis to apoptosis may have a therapeutic value. To determine cell death pathways in pancreatitis and the possibility of necrosis/apoptosis switch, we utilized the differences between the rat model of cerulein pancreatitis, with relatively high apoptosis and low necrosis, and the mouse model, with little apoptosis and high necrosis. We found that caspases were greatly activated during cerulein pancreatitis in the rat but not mouse. Endogenous caspase inhibitor X-linked inhibitor of apoptosis protein (XIAP) underwent complete degradation in the rat but remained intact in the mouse model. Furthermore, XIAP inhibition with embelin triggered caspase activation in the mouse model, implicating XIAP in caspase blockade in pancreatitis. Caspase inhibitors decreased apoptosis and markedly stimulated necrosis in the rat model, worsening pancreatitis parameters. Conversely, caspase induction with embelin stimulated apoptosis and decreased necrosis in mouse model. Thus, caspases not only mediate apoptosis but also protect from necrosis in pancreatitis. One protective mechanism is through degradation of receptor-interacting protein (RIP), a key mediator of "programmed" necrosis. We found that RIP was cleaved (i.e. inactivated) in the rat but not the mouse model. Caspase inhibition restored RIP levels; conversely, caspase induction with embelin triggered RIP cleavage. Our results indicate key roles for caspases, XIAP, and RIP in the regulation of cell death in pancreatitis. Manipulating these signals to change the pattern of death responses presents a therapeutic strategy for treatment of pancreatitis.

Menadione-induced Reactive Oxygen Species Generation via Redox Cycling Promotes Apoptosis of Murine Pancreatic Acinar Cells

“…Furthermore, a recent study in HepG2 cells suggests that cadmium-induced ROS generation may trigger apoptosis via a caspase-dependent pathway (47). Whether the entry of cells into apoptosis is beneficial in the development of acute pancreatitis is currently unresolved, however, several lines of evidence suggest that this may inhibit the formation of cellular necrosis, thereby limiting organ damage and improving disease outcome (17,18,48).…”

“…It has been suggested that while acinar cell necrosis is a key contributor to disease severity, apoptosis protects against the disease (16). Thus, prior induction of pancreatic acinar cell apoptosis protected mice against cerulein-induced pancreatitis (17), while inhibition of caspase activity elicited necrotizing pancreatitis (18). An important potential link between ROS * This work was supported by Medical Research Council Program Grant G8801575.…”

Intracellular Trypsin Induces Pancreatic Acinar Cell Death but Not NF-κB Activation

“…However, this late severe response may have been influenced by prolonged culture of the acini in addition to excessive trypsin activity generated by adenoviral expression. There are also important differences in the sensitivity of acinar cells from different species to apoptotic insults (36). Therefore, it remains unclear which form of cell death may predominate when trypsin is activated intracellularly in human pancreatic acinar cells.…”

Duck Pancreatic Acinar Cell as a Unique Model for Independent Cholinergic Stimulation–Secretion Coupling

“…In mouse embryonic stem cells, hypoxia-induced apoptosis has been found to be inhibited by ACh receptor activation (Kim et al 2008). However, CCK could directly activate caspases in pancreatic acinar cells (Gukovskaya et al 2002;Mareninova et al 2006). Such differences between CCK and ACh receptor signaling may also hold true in duck pancreatic acinar cells.…”